Stabilized pharmaceutical compositions comprising acid donors

ABSTRACT

The invention relates to the use of certain acid donors as stabilizers in pharmaceutical compositions, and to the stabilized pharmaceutical compositions resulting therefrom.

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 07/557,234, filed Jul. 25, 1990.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to the use of certain acid donorsas stabilizers in pharmaceutical compositions, and to the stabilizedpharmaceutical compositions resulting therefrom.

[0003] There are a number of pharmaceutical compositions which sufferfrom instability problems due to the fact that the active component issusceptible to certain types of degradation, thereby diminishing theirattractiveness and, in some cases, rendering them unsuitable from acommercial standpoint. For example, several ACE (Angiotensin ConvertingEnzyme) inhibitor-containing compositions suffer from this drawbacksince certain ACE inhibitors degrade readily in pharmaceutical dosageforms. More particularly, and as is the case with other ACE inhibitorssuch as Quinapril and Enalapril, Spirapril degrades readily in dosageforms to the diketo piperazine (the internal cyclization product) andthe diacid (the ester hydrolysis product). Accordingly, in view of theirusefulness in treating hypertension, a number of research endeavors havebeen directed to overcoming the instability problem associated with ACEinhibitor-containing compositions, without appreciable success.

DESCRIPTION OF THE PRIOR ART

[0004] European Patent Application 264,888 is directed to thestabilization of ACE inhibitor-containing pharmaceutical compositionsemploying ascorbic acid alone or a combination of ascorbic acid withfumaric acid, maleic acid and/or citric acid as the stabilizingcomponent(s).

[0005] U.S. Pat. No. 4,743,450 is also directed to the stabilization ofACE inhibitor-containing pharmaceutical compositions employing, as thestabilizer component, a combination of an alkali or alkaline earth metalsalt (preferably, magnesium carbonate) and a saccharide (preferably,mannitol or lactose).

[0006] Although each of the above patents represents an attempt toovercome the instability problems associated with ACEinhibitor-containing compositions, there still exists a dire need forACE inhibitor-containing compositions exhibiting improved stability,especially in the presence of moisture. To this end, the presentinvention is directed to pharmaceutical compositions, particularly ACEinhibitor-containing compositions, exhibiting improved stability.

OBJECTS OF THE INVENTION

[0007] It is, therefore, an object of the present invention to providenew stabilized pharmaceutical compositions.

[0008] It is another object of the present invention to provide newstabilized pharmaceutical compositions comprising a select group of aciddonors as the stabilizing component thereof.

[0009] It is still another object of the present invention to providenew stabilized ACE inhibitor-containing pharmaceutical compositions.

[0010] It is yet still another object of the present invention toprovide new stabilized ACE inhibitor-containing pharmaceuticalcompositions comprising a select group of acid donors as the stabilizingcomponent thereof.

ADVANTAGES OF THE INVENTION

[0011] The stabilized pharmaceutical compositions of the instantinvention exhibit a number of advantages as follows:

[0012] 1) The active component, e.g., an ACE inhibitor, is virtuallypreserved from any type of degradation.

[0013] 2) They exhibit an extended shelf-life under normal storageconditions.

[0014] 3) They are insensitive to moisture and, in fact, the stabilityimproves with an increase in moisture.

[0015] 4) They exhibit minimal, if any, discoloration over a significantperiod of time.

[0016] 5) They exhibit minimal, if any, instability when employed in thepresence of colorants.

DESCRIPTION OF THE INVENTION

[0017] The attainment of the above objects and advantages is madepossible by the use of certain acid donors and, more particularly, aselect group of hydrochloric acid donors. In comparison to certainacidifiers which have previously been employed as stabilizers inpharmaceutical compositions, e.g., citric acid, maleic acid, ascorbicacid, etc., the acid donors of the present invention release the morevolatile hydrochloric acid and, therefore, effect a greater diffusionthrough the dosage form matrix. Although any compounds which producehydrochloric acid would be suitable in the practice of the instantinvention, preferred acid donors include amino acid hydrochlorides andLewis acid chlorides. The preferred amino acid hydrochlorides areglycine hydrochloride, glutamic acid hydrochloride, betainehydrochloride, alanine hydrochloride, valine hydrochloride, lysinehydrochloride, arginine hydrochloride and aspartic acid hydrochloride,whereas the preferred Lewis acid chlorides are ferric chloride, zincchloride and aluminum chloride. The more preferred amino acidhydrochlorides are glycine hydrochloride, glutamic acid hydrochlorideand betaine hydrochloride, whereas the more preferred Lewis acidchloride is ferric chloride. The most preferred acid donor is glycinehydrochloride.

[0018] Although, in general, the hydrochloric acid donor can be employedin any amount which will prevent degradation of the active component,e.g., an ACE inhibitor, the amount of the hydrochloric acid donoremployed is between 1% and 25%, preferably between 1% and 20%, morepreferably between 1% and 15%, most preferably between 1 and 10%, basedon the total weight of the pharmaceutical composition.

[0019] Although the essence of the instant invention, viz., the use of aselect group of hydrochloric acid donors as stabilizers inpharmaceutical compositions, would apply to all pharmaceuticalcompositions where buffering to a low pH for required stability isessential, it has particularly been found useful when applied to ACEinhibitor-containing pharmaceutical compositions since, as indicatedabove, many ACE inhibitors degrade readily in pharmaceutical dosageforms. In general, all ACE inhibitor-containing pharmaceuticalcompositions wherein the ACE inhibitor employed is prone to formdiketopiperazine degradation products would benefit from the use of aselect group of hydrochloric acid donors as stabilizers therefor. Forexample, one class of ACE inhibitors to which the instant inventionwould apply are compounds of formula I:

[0020] wherein R₁ and R₂, independently, are hydrogen or a group—OC_(n)H_(2n+1), where n is 1 to 5; and

[0021] R₃ is hydrogen or a group —C_(n)H_(2n+1), where n is as definedabove.

[0022] In the above formula, preferred compounds are those where R₁ andR₂ have the same significance. More preferred compounds of the aboveformula are those where R₁ and R₂ are both hydrogen or methoxy and R₃ ishydrogen or methyl. The most preferred compound of the above formula isQuinapril having the formula

[0023] All of the above compounds are known, having been previouslydescribed in U.S. Pat. No. 4,344,949. Moreover, their usefulness intreating hypertension as well as methods for their preparation are setforth therein.

[0024] Another class of ACE inhibitors to which the invention wouldapply are compounds of formula II:

[0025] wherein R is C₁-C₆ alkyl, benzyl, benzylthio, benzyloxy,phenylthio or phenoxy;

[0026] R₁ is hydroxy or C₁-C₆ alkoxy;

[0027] and R₂ is hydrogen, C₁-C₆ alkyl or C₁-C₆ aminoalkyl.

[0028] In the above formula, preferred compounds are those wherein R isbenzyl, R₁is C₁-C₆ alkoxy and R₂ is hydrogen, methyl or aminobutyl. Morepreferred compounds of the above formula are those wherein R is benzyl,R₁ is C₁-C₄ alkoxy and R₂ is hydrogen or methyl. The even more preferredcompounds of the above formula are those wherein R is benzyl, R₁ isethoxy and R₂ is methyl. The most preferred compound of the aboveformula is Enalapril having the formula

[0029] All of the above compounds of formula II are known, having beenpreviously described in European Patent 12,401. Moreover, theirusefulness in treating hypertension as well as methods for theirpreparation are set forth therein.

[0030] A particularly preferred class of ACE inhibitors to which theinstant invention would apply are compounds of formula III:

[0031] wherein R, R₁ and R₂ have the significances indicated aboveregarding the compounds of formula II.

[0032] The preferred, more preferred and even more preferred compoundsof the above formula are as set forth above regarding the compounds offormula II. The most preferred compound of the above formula isSpirapril having the formula

[0033] All of the above compounds of formula III are known, having beenpreviously described in U.S. Pat. No. 4,470,972. Moreover, theirusefulness in treating hypertension as well as methods for theirpreparation are set forth therein.

[0034] It should be noted that all of the compounds of formulae I, IIand III form salts with various inorganic and organic acids and bases,which salts may be prepared by conventional methods. Therefore, itshould be understood that all of such salts would also benefit from theuse of the select group of hydrochloric acid donors as stabilizerstherefor in accordance with the instant invention.

[0035] The amount of the active component, e.g., an ACE inhibitor, inthe stabilized pharmaceutical compositions of the instant invention isbetween 0.5% and 50%, preferably between 0.75% and 25%, more preferablybetween 0.75% and 20%, most preferably between 0.75% and 15%, based onthe total weight of the pharmaceutical composition.

[0036] The weight ratio of the active component, e.g., ACE inhibitor, tothe hydrochloric acid donor may be determined in conventional manner.The preferred weight ratio of the active component to the hydrochloricacid donor is 2.5:1 to 1:7, more preferably 2:1 to 1:2.

[0037] As indicated above, all of the compounds of formulae I, II andIII are known and their usefulness in treating hypertension is also wellknown. Accordingly, the daily dosages at which said compounds areemployed as well as typical unit dosages of said compounds are welldocumented in the literature.

[0038] Although the stabilized ACE inhibitor-containing compositions maybe in any form, the solid forms are preferred, more preferably tablets,capsules and caplets.

[0039] In addition to the active component, e.g., an ACE inhibitor, andthe stabilizing component, e.g., glycine hydrochloride, the stabilizedcompositions of the instant invention will typically contain apharmaceutically acceptable carrier. Generally, they are compounds whichdo not contain groups which would significantly interfere with eitherthe active component or the stabilizing component. For example, sugarssuch as lactose, sucrose, mannitol and sorbitol are quite suitable; asare starches such as corn starch and tapioca starch; cellulose andderivatives thereof such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; calcium phosphates such as dicalciumphosphate; sodium sulfate; and polyvinyl alcohol. Such type compoundsare generally present in amounts of between 5% and 90%, preferablybetween 10% and 80%, based on the total weight of the pharmaceuticalcomposition.

[0040] The stabilized compositions of the instant invention may alsocontain optional ingredients that are normally employed inpharmaceutical formulations, the only qualification being that they mustbe compatible with the select group of hydrochloric acid donors so asnot to interfere with their stabilizing function. Typical optionalingredients include lubricants, e.g., talc, alkaline earth metalstearates such as magnesium stearate and calcium stearate, andhydrogenated vegetable oils such as hydrogenated cottonseed oil; binderssuch as polyvinylpyrrolidone and gelatin; and disintegrants such asmicrocrystalline cellulose, cross-linked polyvinyl-pyrrolidone andalginic acid. Other optional ingredients are fillers, water scavengers,buffers, preservatives, anti-oxidants, colorants and flavoring agents.The total amount of the optional ingredients in the stabilizedcompositions of the instant invention is not critical. In general, thetotal amount of the optional ingredients is consistent with the amountof the active component, stabilizer and pharmaceutically acceptablecarrier, i.e., the total amount will be equivalent to the remainder ofthe pharmaceutical compositions.

[0041] The stabilized compositions of the instant invention can beprepared by any of the conventionally employed processing techniquessuch as the wet granulation process. The technique is preferably chosento ensure a homogeneous distribution of the active component and ahomogeneous distribution of the hydrochloric acid donor over or amongthe active component particles. Conveniently, the hydrochloric aciddonor is distributed in a liquid form, e.g. an aqueous solution used asa granulating liquid.

[0042] Other active components that are contemplated include those witha —NH—CH—CO—N—C—COOH moiety as in the above formulae I, II and III,e.g., the diacid form of Spirapril, viz., Spiraprilate. Such compoundsinclude Ramipril, Perindopril, Indolapril, Lisinopril, Alacepril,Trandolapril, Benazapril, Libenzapril, Delapril and Cilazapril.

[0043] The following examples are for the purpose of illustration onlyand are not intended in any way to limit the scope of the instantinvention.

EXAMPLE 1

[0044] Below are stabilized compositions in accordance with the instantinvention in white tablet form: Amount (mg) Ingredient A B Quinaprilhydrochloride 40.0 — Enalapril hydrochloride — 40.0 glycinehydrochloride 40.0 40.0 lactose 277.5 277.5 corn starch 25.0 25.0 talc15.0 15.0 magnesium stearate 2.5 2.5 total 400.0 400.0

EXAMPLE 2

[0045] The following compositions A-D represent stabilized compositionsin accordance with the instant invention in white tablet form whereascomposition E does not contain a stabilizer of the instant invention:Amount (mg) Ingredient A B C D E Spirapril hydrochloride 3.06 3.06 3.063.06 3.19 lactose, NF 99.94 94.74 99.94 94.74 80.21 starch, NF 19.5019.50 19.50 19.50 12.00 povidone, USP 2.60 2.60 2.60 2.60 2.00 glycinehydrochloride — — 2.60 2.60 — glutamic acid hydro- 2.60 2.60 — — —chloride silica gel, NF — 5.20 — 5.20 1.90 colloidal SiO₂, NF 1.30 1.301.30 1.30 0.10 magnesium stearate, NF 1.00 1.00 1.00 1.00 0.60 total130.00 130.00 130.00 130.00 100.00

EXAMPLE 3

[0046] To demonstrate the effectiveness of the stabilizers of theinstant invention against added moisture, the following results wereobtained when the compositions of Examples 2A-2D were stored for 3months at 30° C. and 75% relative humidity: *Assay % Diketo DiacidExample 2A 99.6 0.0 0.1 Example 2B 100.0 0.0 0.2 Example 2C 99.6 0.0 0.1Example 2D 99.9 0.0 0.2

EXAMPLE 4

[0047] To demonstrate the effectiveness of the stabilizers of theinstant invention against an increase in temperature, the followingresults were obtained when the compositions of Example 2A and 2C werestored at 50° C. for varying periods of time. For purposes ofcomparison, below are the results obtained when the composition ofExample 2E was stored at 50° C. for three months. Period (months) *Assay% Diketo Diacid Example 2A 1 99.0 0.2 0.1 2 100.8 0.6 0.3 3 99.1 0.9 0.3Example 2C 1 100.3 0.1 0.2 2 101.3 0.8 0.2 3 98.4 1.0 0.3 Example 2E 391.2 7.3 0.4

EXAMPLE 5

[0048] The following compositions A, B and D represent stabilizedcompositions in accordance with the instant invention in colored tabletform whereas composition C contains maleic acid, an acidifier disclosedin the prior art: Amount (mg) Ingredient A B C D Spirapril hydrochloride3.06 3.06 3.06 6.00 lactose, NF 96.94 96.94 96.94 99.77 starch, NF 19.5019.50 19.50 22.50 povidone, USP 2.60 2.60 2.60 3.00 alginic acid — — —13.00 glycine hydrochloride 2.60 — — 3.00 glutamic acid hydrochloride —2.60 — — maleic acid — — 2.60 — carmine 3.00 3.00 3.00 — iron oxide, red— — — 0.03 colloidol SiO₂, NF 1.30 1.30 1.30 1.50 magnesium stearate, NF1.00 1.00 1.00 1.20 total 130.00 130.00 130.00 150.00

EXAMPLE 6

[0049] To demonstrate the effectiveness of the stabilizers of theinstant invention against an increase in temperature in the presence ofcolorants, the following results were obtained when the carmine coloredcompositions of Examples 5A and 5B were stored at 50° C. for threemonths. *Assay % Diketo Diacid Example 5A 96.3 2.7 ** Example 5B 96.01.8 **

EXAMPLE 7

[0050] To demonstrate that volatile acids such as hydrochloric acid aremore effective stabilizers than non-volatile acids such as maleic acid,the following results were obtained when the compositions of Examples 5Aand 5C were stored at 50° C. for varying periods of time: Period(months) *Assay % Diketo **Diacid Example 5A 1 98.4 1.1 1 2 105.2 3.1 23 96.3 2.7 2 Example 5C 1 91.6 5.1 1 2 89.2 14.8 2 3 84.6 10.0 2

EXAMPLE 8

[0051] The following compositions A-D represent stabilized compositionsin accordance with the instant invention in white tablet form whereascomposition E does not contain a stabilizer of the instant invention:Amount (mg) Ingredient A B C D E Spirapril hydrochloride 3.3 3.3 3.3 3.33.3 lactose, NF 360.0 360.0 360.0 360.0 360.0 glycine hydrochloride 20.0— — — — ferric chloride — 20.0 — — — betaine hydrochloride — — 20.0 — —glutamic acid hydro- — — — 20.0 — chloride colloidal SiO₂, NF 1.0 1.01.0 1.0 1.0 stearic acid, NF 16.0 16.0 16.0 16.0 16.0 total 400.3 400.3400.3 400.3 380.3

EXAMPLE 9

[0052] To demonstrate the effectiveness of the stabilizers of theinstant invention against an increase in temperature and added moisture,the following results were obtained when the compositions of Examples8A-8D were stored for 72 hours. For purposes of comparison, below arethe results obtained when the composition of Example 8E was stored for72 hours under the same conditions. Temp. (° C.) % Water *Assay % DiketoDiacid Example 8A 0 0 94 0.1 0.10 65 0 91 0.6 0.05 65 5 — — — 65 10 920.7 0.10 Example 8B 0 0 62 0.3 0.80 65 0 66 0.4 0.60 65 5 72 0.7 1.40 6510 66 1.3 3.10 Example 8C 0 0 94 0.1 0.40 65 0 91 4.0 0.03 65 5 94 0.90.07 65 10 95 0.8 0.14 Example 8D 0 0 95 0.2 0.03 65 0 91 3.6 0.03 65 597 0.4 0.10 65 10 94 0.4 0.20 Example 8E 0 0 93 0.1 0.05 65 0 87 6.00.04 65 5 79 9.0 0.20 65 10 65 17.0  0.30

EXAMPLE 10

[0053] To demonstrate the extended shelf-life of a stabilizedcomposition in accordance with the instant invention, the followingresults were obtained when the composition of Example 5A was stored foran extended period under various conditions: Period 30° C. 40° C. 50° C.30° C./75% RH (months) DK DA DK DA DK DA DK DA 0 0.4 0.0 — — — — — — 30.4 0.1 1.3 0.2 2.5 0.2 0.4 0.1 6 0.5 0.2 1.7 0.2 3.0 0.1 0.5 0.1 9 0.90.2 — — — — — — 12 1.1 0.2 2.6 0.1 — — — — 24 1.5 0.2 — — — — — —

What is claimed is:
 1. A method of stabilizing a pharmaceuticalcomposition containing an active component subject to degradationcomprising incorporating therein a stabilizing effective amount of ahydrochloric acid donor.
 2. A method according to claim 1 wherein theactive component is an ACE inhibitor.
 3. A method according to claim 2wherein the ACE inhibitor is a compound of formula I:

wherein R₁ and R₂, independently, are hydrogen or a group—OC_(n)H_(2n+1), where n is 1 to 5; and R₃ is hydrogen or a group—C_(n)H_(2n+1), where n is as defined above; or a pharmaceuticallyacceptable salt thereof.
 4. A method according to claim 3 wherein theACE inhibitor is a compound of formula I wherein R₁ and R₂ have the samesignificance, or a pharmaceutically acceptable salt thereof.
 5. A methodaccording to claim 4 wherein the ACE inhibitor is a compound of formulaI wherein R₁ and R₂ are both hydrogen or methoxy and R₃ is hydrogen ormethyl, or a pharmaceutically acceptable salt thereof.
 6. A methodaccording to claim 5 wherein the ACE inhibitor is a compound having theformula

or a pharmaceutically acceptable salt thereof.
 7. A method according toclaim 2 wherein the ACE inhibitor is a compound of formula II:

wherein R is C₁-C₆ alkyl, benzyl, benzylthio, benzyloxy, phenylthio orphenoxy; R₁ is hydroxy or C₁-C₆ alkoxy; and R₂ is hydrogen, C₁-C₆ alkylor C₁-C₆ aminoalkyl; or a pharmaceutically acceptable salt thereof.
 8. Amethod according to claim 7 wherein the ACE inhibitor is a compound offormula II wherein R is benzyl, R₁ is C₁-C₆ alkoxy and R₂ is hydrogen,methyl or aminobutyl, or a pharmaceutically acceptable salt thereof. 9.A method according to claim 8 wherein the ACE inhibitor is a compound offormula II wherein R is benzyl, R₁ is C₁-C₄ alkoxy and R₂ is hydrogen ormethyl, or a pharmaceutically acceptable salt thereof.
 10. A methodaccording to claim 9 wherein the ACE inhibitor is a compound of formulaII wherein R is benzyl, R₁ is ethoxy and R₂ is methyl, or apharmaceutically acceptable salt thereof.
 11. A method according toclaim 10 wherein the ACE inhibitor is a compound having the formula

or a pharmaceutically acceptable salt thereof.
 12. A method according toclaim 2 wherein the ACE inhibitor is a compound of formula III:

wherein R is C₁-C₆ alkyl, benzyl, benzylthio, benzyloxy, phenylthio orphenoxy; R₁ is hydroxy or C₁-C₆ alkoxy; and R₂ is hydrogen, C₁-C₆ alkylor C₁-C₆ aminoalkyl; or a pharmaceutically acceptable salt thereof. 13.A method according to claim 12 wherein the ACE inhibitor is a compoundof formula III wherein R is benzyl, R₁ is C₁-C₆ alkoxy and R₂ ishydrogen, methyl or aminobutyl, or a pharmaceutically acceptable saltthereof.
 14. A method according to claim 13 wherein the ACE inhibitor isa compound of formula III wherein R is benzyl, R₁ is C₁-C₄ alkoxy and R₂is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.15. A method according to claim 14 wherein the ACE inhibitor is acompound of formula III wherein R is benzyl, R₁ is ethoxy and R₂ ismethyl, or a pharmaceutically acceptable salt thereof.
 16. A methodaccording to claim 15 wherein the ACE inhibitor is a compound having theformula

or a pharmaceutically acceptable salt thereof.
 17. A method according toclaim 1 wherein the hydrochloric acid donor is an amino acidhydrochloride or a Lewis acid chloride.
 18. A method according to claim17 wherein the amino acid hydrochloride is selected from the groupconsisting of glycine hydrochloride, glutamic acid hydrochloride,betaine hydrochloride, alanine hydrochloride, valine hydrochloride,lysine hydrochloride, arginine hydrochloride and aspartic acidhydrochloride.
 19. A method according to claim 18 wherein the amino acidhydrochloride is selected from the group consisting of glycinehydrochloride, glutamic acid hydrochloride and betaine hydrochloride.20. A method according to claim 19 wherein the amino acid hydrochlorideis glycine hydrochloride.
 21. A method according to claim 17 wherein theLewis acid chloride is selected from the group consisting of ferricchloride, zinc chloride and aluminum chloride.
 22. A method according toclaim 21 wherein the Lewis acid chloride is ferric chloride.
 23. Amethod according to claim 17 wherein the hydrochloric acid donor ispresent in an amount between 1% and 25%, based on the total weight ofthe composition.
 24. A method according to claim 23 wherein thehydrochloric acid donor is present in an amount between 1% and 20%,based on the total weight of the composition.
 25. A method according toclaim 24 wherein the hydrochloric acid donor is present in an amountbetween 1% and 15%, based on the total weight of the composition.
 26. Amethod according to claim 25 wherein the hydrochloric acid donor ispresent in an amount between 1% and 10%, based on the total weight ofthe composition.
 27. A method of stabilizing a pharmaceuticalcomposition containing an ACE inhibitor having the formula

or a pharmaceutically acceptable salt thereof, comprising incorporatingtherein, as a stabilizer therefor, between 1% and 25% of glycinehydrochloride, based on the total weight of the composition.
 28. Astabilized pharmaceutical composition comprising an active componentsubject to degradation and, as a stabilizer therefor, a hydrochloricacid donor.
 29. A stabilized composition according to claim 28 whereinthe active component is an ACE inhibitor.
 30. A stabilized compositionaccording to claim 29 wherein the ACE inhibitor is a compound of formulaI:

wherein R₁ and R₂, independently, are hydrogen or a group—OC_(n)H_(2n+1), where n is 1 to 5; and R₃ is hydrogen or a group—C_(n)H_(2n+1), where n is as defined above; or a pharmaceuticallyacceptable salt thereof.
 31. A stabilized composition according to claim30 wherein the ACE inhibitor is a compound of formula I wherein R₁ andR₂ have the same significance, or a pharmaceutically acceptable saltthereof.
 32. A stabilized composition according to claim 31 wherein theACE inhibitor is a compound of formula I wherein R₁ and R₂ are bothhydrogen or methoxy and R₃ is hydrogen or methyl, or a pharmaceuticallyacceptable salt thereof.
 33. A stabilized composition according to claim32 wherein the ACE inhibitor is a compound having the formula

or a pharmaceutically acceptable salt thereof.
 34. A stabilizedcomposition according to claim 29 wherein the ACE inhibitor is acompound of formula II:

wherein R is C₁-C₆ alkyl, benzyl, benzylthio, benzyloxy, phenylthio orphenoxy; R₁ is hydrogen or C₁-C₆ alkoxy; and R₂ is hydrogen, C₁-C₆ alkylor C₁-C₆ aminoalkyl; or a pharmaceutically acceptable salt thereof. 35.A stabilized composition according to claim 34 wherein the ACE inhibitoris a compound of formula II wherein R is benzyl, R₁ is C₁-C₆ alkoxy andR₂ is hydrogen, methyl or aminobutyl, or a pharmaceutically acceptablesalt thereof.
 36. A stabilized composition according to claim 35 whereinthe ACE inhibitor is a compound of formula II wherein R is benzyl, R₁ isC₁-C₄ alkoxy and R₂ is hydrogen or methyl, or a pharmaceuticallyacceptable salt thereof.
 37. A stabilized composition according to claim36 wherein the ACE inhibitor is a compound of formula II wherein R isbenzyl, R₁ is ethoxy and R₂ is methyl, or a pharmaceutically acceptablesalt thereof.
 38. A stabilized composition according to claim 37 whereinthe ACE inhibitor is a compound having the formula

or a pharmaceutically acceptable salt thereof.
 39. A stabilizedcomposition according to claim 29 wherein the ACE inhibitor is acompound of formula III:

wherein R is C₁-C₆ alkyl, benzyl, benzylthio, benzyloxy, phenylthio orphenoxy; R₁ is hydroxy or C₁-C₆ alkoxy; and R₂ is hydrogen, C₁-C₆ alkylor C₁-C₆ aminoalkyl; or a pharmaceutically acceptable salt thereof. 40.A stabilized composition according to claim 39 wherein the ACE inhibitoris a compound of formula III wherein R is benzyl, R₁ is C₁-C₆ alkoxy andR₂ is hydrogen, methyl or aminobutyl, or a pharmaceutically acceptablesalt thereof.
 41. A stabilized composition according to claim 40 whereinthe ACE inhibitor is a compound of formula III wherein R is benzyl, R isC₁-C₄ alkoxy and R₂ is hydrogen or methyl, or a pharmaceuticallyacceptable salt thereof.
 42. A stabilized composition according to claim41 wherein the ACE inhibitor is a compound of formula III wherein R isbenzyl, R₁ is ethoxy and R₂ is methyl, or a pharmaceutically acceptablesalt thereof.
 43. A stabilized composition according to claim 42 whereinthe ACE inhibitor is a compound having the formula

or a pharmaceutically acceptable salt thereof.
 44. A stabilizedcomposition according to claim 28 wherein the hydrochloric acid donor isan amino acid hydrochloride or a Lewis acid chloride.
 45. A stabilizedcomposition according to claim 44 wherein the amino acid hydrochlorideis selected from the group consisting of glycine hydrochloride, glutamicacid hydrochloride, betaine hydrochloride, alanine hydrochloride, valinehydrochloride, lysine hydrochloride, arginine hydrochloride and asparticacid hydrochloride.
 46. A stabilized composition according to claim 45wherein the amino acid hydrochloride is selected from the groupconsisting of glycine hydrochloride, glutamic acid hydrochloride andbetaine hydrochloride.
 47. A stabilized composition according to claim46 wherein the amino acid hydrochloride is glycine hydrochloride.
 48. Astabilized composition according to claim 44 wherein the Lewis acidchloride is selected from the group consisting of ferric chloride, zincchloride and aluminum chloride.
 49. A stabilized composition accordingto claim 48 wherein the Lewis acid chloride is ferric chloride.
 50. Astabilized composition according to claim 44 wherein the hydrochloricacid donor is present in an amount between 1% and 25%, based on thetotal weight of the composition.
 51. A stabilized composition accordingto claim 50 wherein the hydrochloric acid donor is present in a amountbetween 1% and 20%, based on the total weight of the composition.
 52. Astabilized composition according to claim 51 wherein the hydrochloricacid donor is present in an amount between 1% and 15%, based on thetotal weight of the composition.
 53. A stabilized composition accordingto claim 52 wherein the hydrochloric acid donor is present in an amountbetween 1% and 10%, based on the total weight of the composition.
 54. Astabilized pharmaceutical composition comprising an ACE inhibitor havingthe formula

or a pharmaceutically acceptable salt thereof and, as a stabilizertherefor, between 1% and 25% of glycine hydrochloride, based on thetotal weight of the composition.